CONFORMATIONALLY DEFINED NEUROTRANSMITTER ANALOGS - SELECTIVE-INHIBITION OF GLUTAMATE UPTAKE BY ONE PYRROLIDINE-2,4-DICARBOXYLATE DIASTEREOMER
CONFORMATIONALLY DEFINED NEUROTRANSMITTER ANALOGS - SELECTIVE-INHIBITION OF GLUTAMATE UPTAKE BY ONE PYRROLIDINE-2,4-DICARBOXYLATE DIASTEREOMER
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DOI：
10.1021/jm00106a037
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发表时间：
1991-02-01
影响因子：
7.3
通讯作者：
CHAMBERLIN, AR
中科院分区：
文献类型：
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作者：
BRIDGES, RJ;STANLEY, MS;CHAMBERLIN, AR
为了确定L-谷氨酸与参与神经传递过程的蛋白质结合的构象要求，制备了含有嵌入谷氨酸部分的刚性类似物。 这些“构象模拟物”，即吡咯烷-2,4-二羧酸盐 4、7、11 和 14，是由市售的反式-4-羟基-L-脯氨酸和顺式-4-羟基-D-脯氨酸合成的，然后测试它们抑制 [H-3]-L-谷氨酸高亲和力转运到突触体中并阻断放射性配体与突触体结合的能力。 NMDA（N-甲基-D-天冬氨酸）、KA（红藻氨酸）和 QA（quisqualate）谷氨酸神经递质受体位点。 虽然四种类似物均不能有效结合兴奋性受体，但 L-反式异构体 7 是一种有效的、选择性的 L-谷氨酸转运竞争性抑制剂。 这些结果描绘了与摄取系统结合的特定结构/构象偏好，这与与 NMDA、KA 和 QA 受体结合所需的偏好不同。
In order to determine the conformational requirements for binding of L-glutamate to the proteins involved in the process of neurotransmission, rigid analogues containing an embedded glutamate moiety have been prepared. These ''conformer mimics'', the pyrrolidine-2,4-dicarboxylates 4, 7, 11, and 14, were synthesized from commercially available trans-4-hydroxy-L-proline and cis-4-hydroxy-D-proline, and then were tested for their ability to inhibit the high-affinity transport of [H-3]-L-glutamate into synaptosomes and to block the binding of radioligands to the NMDA (N-methyl-D-aspartate), KA (kainate), and QA (quisqualate) glutamate neurotransmitter receptor sites. While none of the four analogues binds effectively to the excitatory receptors, the L-trans-isomer 7 is a potent and selective competitive inhibitor of L-glutamate transport. These results delineate a specific structural/conformational preference for binding to the uptake system that is distinct from that required for binding to the NMDA, KA, and QA receptors.